LDHA Desuccinylase Sirtuin 5 as a Novel Cancer Metastatic Stimulator in Aggressive Prostate Cancer

Abstract

Prostate cancer (PCa) is the most commonly diagnosed genital cancer in men worldwide. Around 80% of the patients who developed advanced PCa suffered from bone metastasis, with a sharp drop in the survival rate. Despite great efforts, the detailed mechanisms underlying castration-resistant PCa (CRPC) remain unclear. Sirtuin 5 (SIRT5), an NAD+-dependent desuccinylase, is hypothesized to be a key regulator of various cancers. However, compared to other SIRTs, the role of SIRT5 in cancer has not been extensively studied. Here, we revealed significantly decreased SIRT5 levels in aggressive PCa cells relative to the PCa stages. The correlation between the decrease in the SIRT5 level and the patient’s reduced survival rate was also confirmed. Using quantitative global succinylome analysis, we characterized a significant increase in the succinylation at lysine 118 (K118su) of lactate dehydrogenase A (LDHA), which plays a role in increasing LDH activity. As a substrate of SIRT5, LDHA-K118su significantly increased the migration and invasion of PCa cells and LDH activity in PCa patients. This study reveals the reduction of SIRT5 protein expression and LDHA-K118su as a novel mechanism involved in PCa progression, which could serve as a new target to prevent CPRC progression for PCa treatment.

The Mechanistic Roles of Sirtuins in Breast and Prostate Cancer

“…As in breast cancer, SIRT5 was found to be highly expressed in prostate tumor tissues compared to normal prostate tissues [ 99 ]. However, in contrast, recent studies have revealed that SIRT5 expression is downregulated in advanced prostate cancer [ 100 , 101 ], suggesting that SIRT5 downregulation is dependent on the progression or stage of the prostate cancer cells. These findings may indicate a tumor-stage-dependent role of SIRT5 in prostate carcinogenesis.…”

“…Conversely, a more recent study demonstrated that SIRT5 expression reduces the migration and invasion of PC3 prostate cancer cells [ 101 ]. This was found to occur via SIRT5 desuccinylation of LDHA to reduce its activity, culminating in the growth reduction and survival of prostate cancer cells [ 101 ].…”

“…Conversely, a more recent study demonstrated that SIRT5 expression reduces the migration and invasion of PC3 prostate cancer cells [ 101 ]. This was found to occur via SIRT5 desuccinylation of LDHA to reduce its activity, culminating in the growth reduction and survival of prostate cancer cells [ 101 ]. Consistent with this finding, another recent study demonstrated that SIRT5 suppressed the progression of PC3 prostate cancer cells by downregulating the PI3K/AKT/NK-kB pathway [ 100 ].…”

Therapeutic Potential and Activity Modulation of the Protein Lysine Deacylase Sirtuin 5

“…Nonetheless, no mechanistic insight was provided regarding the role of LDHA in the onset and progression of prostate cancer. 132 …”

“…The observed effects were ascribed to the higher activity of lactate dehydrogenase (LDH) A, which is activated upon succinylation at Lys118 and is a demonstrated substrate of SIRT5. Nonetheless, no mechanistic insight was provided regarding the role of LDHA in the onset and progression of prostate cancer …”